Late developmental regulation in Chlamydia

项目摘要/摘要 衣原体是危害人类健康的重要病原体之一。 透视。2014年，报告了140多万例衣原体感染病例 使其成为美国最常见的传染病。 衣原体引起一种不寻常的细胞内感染，在这种感染中，有两种特殊的 细菌在受感染细胞内的形态。网状小体(RB)是细胞内的 通过多轮二元裂变进行复制的形式。然后在最后一个阶段 细胞内感染，每个RB异步转化为基本体(EB)， 这是一种将感染传播到新细胞的感染形式。我们建议 研究这种从RB到EB的后期发育变化是如何通过聚焦来调节的 在感染后期上调的一小群衣原体基因上。 我们有证据表明，这些晚期基因受到负调控，以防止其 过早的表达。在目标1中，我们将研究一种名为euo to的转录调控因子 了解它对晚期基因的抑制是如何在后期解除的，从而允许这些基因 被表达出来。我们假设EuO是以依赖于氧化还原的方式转化的 从二聚体转变为单体，然后通过蛋白质降解进行降解。在目标2中，我们将 研究另一种称为RsbW的调节子，我们认为它是信号通路的一部分 控制由σ28RNA聚合酶转录的晚期基因的子集 对葡萄糖供应的反应。AIM 3将使用共聚焦显微镜来检查这些 单个感染个体RBS和EBS的晚期基因调控机制 手机。我们将调查晚期基因表达的调节者是否也控制Rb- TO-EB转换以及为什么这一关键转换步骤是异步进行的。这些 研究有可能导致治疗衣原体的新治疗策略 通过中断这一关键的转换步骤并防止产生 感染性细菌。

Project Summary/Abstract Chlamydia is one of the most important infectious agents from a public health perspective. In 2014 more than 1.4 million cases of chlamydial infections were reported to the CDC making it the most commonly reported infectious disease in the U.S. Chlamydia causes an unusual intracellular infection in which there are two specialized forms of the bacterium within an infected cell. The reticulate body (RB) is an intracellular form that replicates via multiple rounds of binary fission. Then at a late stage in the intracellular infection, each RB asynchronously converts into an elementary body (EB), which is the infectious form that transmits the infection to a new cell. We propose to study how this late developmental change from an RB to an EB is regulated by focusing on a small group of chlamydial genes that are upregulated at late times in the infection. We have evidence that these late genes are negatively regulated to prevent their premature expression. In Aim 1, we will study a transcriptional regulator called EUO to understand how its repression of late genes is relieved at late times to allow these genes to be expressed. We hypothesize that EUO is converted in a redox-dependent manner from a dimer into a monomer that is then degraded by proteolysis. In Aim 2, we will study another regulator called RsbW, which we propose is part of a signaling pathway that controls the transcription of a subset of late genes by σ28 RNA polymerase in response to glucose availability. Aim 3 will use confocal microscopy to examine these mechanisms of late gene regulation in individual RBs and EBs within a single infected cell. We will investigate whether the regulators of late gene expression also control RB- to-EB conversion and why this critical conversion step occurs asynchronously. These studies have the potential to lead to novel therapeutic strategies for treating chlamydial infections by interrupting this critical conversion step and preventing the production of infectious bacteria.